This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. IgA proteases were discovered in 1975 by our collaborator Andrew Palut. These enzymes are bacterial endopeptidases of several different protease types produced by medically important pathogenic bacteria in the genera Streptococcus, Neisseria, Haemophilus, Ureaplasma, Clostridia, Capnocytophaga and Bacteroides. Each enzyme consists of a single, non-glycosylated, water soluble polypeptide chain. All IgA proteases have pronounced substrate specificity for human immunoglobulin IgA1. Each enzyme cleaves a single, specific peptide bond in the heavy polypeptide chain hinge region. Of extreme interest is the mechanism of high selectivity exhibited by these enzymes such that the highly homologous human IgA2 immunoglobulin is not a substrate. The enzyme is large (110kDa) and we postulate that unlike typical endopeptidases, substrate recognition is not based upon a primary consensus sequence. In contrast we believe that these proteases achieve their high degree of selectivity via 3-D recognition of the IgA1 molecule and subsequently mediate cleavage in the unstructured hinge region. This mechanism is similar to that of SUMO-protease. There is currently no structural information on any proteins of this class of proteases and therefore the current structural investigation is of great importance.